Heterodimerization With 5-HT2BR Is Indispensable for β2AR-Mediated Cardioprotection
RATIONALE: The β2-adrenoceptor (β2-AR), a prototypical GPCR (G protein-coupled receptor), couples to both Gs and Gi proteins. Stimulation of the β2-AR is beneficial to humans and animals with heart failure presumably because it activates the downstream Gi-PI3K-Akt cell survival pathway. Cardiac β2-AR signaling can be regulated by crosstalk or heterodimerization with other GPCRs, but the physiological and pathophysiological significance of this type of regulation has not been sufficiently demonstrated.
OBJECTIVE: Here, we aim to investigate the potential cardioprotective effect of β2-adrenergic stimulation with a subtype-selective agonist, (R,R')-4-methoxy-1-naphthylfenoterol (MNF), and to decipher the underlying mechanism with a particular emphasis on the role of heterodimerization of β2-ARs with another GPCR, 5-hydroxytryptamine receptors 2B (5-HT2BRs).
METHODS AND RESULTS: Using pharmacological, genetic and biophysical protein-protein interaction approaches, we studied the cardioprotective effect of the β2-agonist, MNF, and explored the underlying mechanism in both in vivo in mice and cultured rodent cardiomyocytes insulted with doxorubicin, hydrogen peroxide (H2O2) or ischemia/reperfusion. In doxorubicin (Dox)-treated mice, MNF reduced mortality and body weight loss, while improving cardiac function and cardiomyocyte viability. MNF also alleviated myocardial ischemia/reperfusion injury. In cultured rodent cardiomyocytes, MNF inhibited DNA damage and cell death caused by Dox, H2O2 or hypoxia/reoxygenation. Mechanistically, we found that MNF or another β2-agonist zinterol markedly promoted heterodimerization of β2-ARs with 5-HT2BRs. Upregulation of the heterodimerized 5-HT2BRs and β2-ARs enhanced β2-AR-stimulated Gi-Akt signaling and cardioprotection while knockdown or pharmacological inhibition of the 5-HT2BR attenuated β2-AR-stimulated Gi signaling and cardioprotection.
CONCLUSIONS: These data demonstrate that the β2-AR-stimulated cardioprotective Gi signaling depends on the heterodimerization of β2-ARs and 5-HT2BRs.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:128 |
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| Enthalten in: |
Circulation research - 128(2021), 2 vom: 22. Jan., Seite 262-277 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Song, Ying [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.07.2021 Date Revised 26.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1161/CIRCRESAHA.120.317011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Song, Ying |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Heterodimerization With 5-HT2BR Is Indispensable for β2AR-Mediated Cardioprotection |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a RATIONALE: The β2-adrenoceptor (β2-AR), a prototypical GPCR (G protein-coupled receptor), couples to both Gs and Gi proteins. Stimulation of the β2-AR is beneficial to humans and animals with heart failure presumably because it activates the downstream Gi-PI3K-Akt cell survival pathway. Cardiac β2-AR signaling can be regulated by crosstalk or heterodimerization with other GPCRs, but the physiological and pathophysiological significance of this type of regulation has not been sufficiently demonstrated | ||
| 520 | |a OBJECTIVE: Here, we aim to investigate the potential cardioprotective effect of β2-adrenergic stimulation with a subtype-selective agonist, (R,R')-4-methoxy-1-naphthylfenoterol (MNF), and to decipher the underlying mechanism with a particular emphasis on the role of heterodimerization of β2-ARs with another GPCR, 5-hydroxytryptamine receptors 2B (5-HT2BRs) | ||
| 520 | |a METHODS AND RESULTS: Using pharmacological, genetic and biophysical protein-protein interaction approaches, we studied the cardioprotective effect of the β2-agonist, MNF, and explored the underlying mechanism in both in vivo in mice and cultured rodent cardiomyocytes insulted with doxorubicin, hydrogen peroxide (H2O2) or ischemia/reperfusion. In doxorubicin (Dox)-treated mice, MNF reduced mortality and body weight loss, while improving cardiac function and cardiomyocyte viability. MNF also alleviated myocardial ischemia/reperfusion injury. In cultured rodent cardiomyocytes, MNF inhibited DNA damage and cell death caused by Dox, H2O2 or hypoxia/reoxygenation. Mechanistically, we found that MNF or another β2-agonist zinterol markedly promoted heterodimerization of β2-ARs with 5-HT2BRs. Upregulation of the heterodimerized 5-HT2BRs and β2-ARs enhanced β2-AR-stimulated Gi-Akt signaling and cardioprotection while knockdown or pharmacological inhibition of the 5-HT2BR attenuated β2-AR-stimulated Gi signaling and cardioprotection | ||
| 520 | |a CONCLUSIONS: These data demonstrate that the β2-AR-stimulated cardioprotective Gi signaling depends on the heterodimerization of β2-ARs and 5-HT2BRs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a GTP-binding protein alpha subunits, gi-go | |
| 650 | 4 | |a doxorubicin | |
| 650 | 4 | |a myocardial reperfusion injury | |
| 650 | 4 | |a myocytes, cardiac | |
| 650 | 4 | |a protein multimerization | |
| 650 | 4 | |a receptor, serotonin, 5-HT2B | |
| 650 | 4 | |a receptors, adrenergic, beta-2 | |
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| 700 | 1 | |a Xu, Chanjuan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jianfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yulong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Huan |e verfasserin |4 aut | |
| 700 | 1 | |a Shan, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Wainer, Irving W |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Xinli |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Woo, Anthony Yiu-Ho |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Rui-Ping |e verfasserin |4 aut | |
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